Inherited deficiencies in man of the enzymes adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) have been found to be associated with patients having severe combined immunodeficiency disease (SCID) and a T cell deficiency, respectively. These specific immunodeficiencies are thought to arise from blocks in lymphocyte differentiation caused by the effects of the specific enzyme deficiency. However, little is known about the stage or stages of lymphocyte development which are affected by the enzyme deficiency nor is it known what biochemical mechanisms are responsible for the selective pathogenicity of the immune system. The major objectives of this proposal are to identify in the normal rat lymphoid system and in the regenerating lymphoid system after irradiation what cell populations within the rat T and B lymphocyte developmental lineage are preferentially affected by an induced adenosine deaminase deficiency. In vitro correlative studies will also be performed using fetal organ cultures and rat leukemic cell culture lines representing differing stages of differentiation. Once having identified the sensitive populations we will isolate and compare sensitive and insensitive in vivo and in vitro lymphoid populations for various enzymatic and metabolic characteristics which are potentially responsible for the selective pathogenicity of the immune system.